The present invention relates generally to a process for limiting the penetration into the skin and/or the keratinous fibres of at least one cosmetically and/or pharmaceutically active agent present in a base cosmetic and/or pharmaceutical composition for topical application and in particular for reducing the rate of penetration into the skin and/or the keratinous fibres of the active agent(s).
Numerous families of compounds are known which have the property of activating the penetration into the skin or the keratinous fibres of an active agent present in a cosmetic and/or pharmaceutical composition. Thus, U.S. Pat. No. 4,960,771 discloses the use, in cosmetic or pharmaceutical compositions, of oxazolidinone derivatives for increasing the penetration of active agents in the broadest sense. The use of amides for increasing this penetration is disclosed in U.S. Pat. No. 5,162,315.
U.S. Pat. Nos. 4,837,026, 4,876,249 and 5,030,629 disclose cyclic derivatives which promote the penetration of active agents.
On the other hand, very few families of compounds are known which possess the reverse activity, that is to say effectively reducing the penetration of an active agent of a cosmetic and/or pharmaceutical composition into the skin and/or the keratinous fibres.
However, some oxazolidinone derivatives exhibit this property.
It would be desirable to have available compounds or formulations having properties of reducing the penetration into the skin and/or the keratinous fibres of active agents of cosmetic and/or pharmaceutical compositions.
This is because, for certain cosmetic and/or pharmaceutical formulations for application to the skin and/or the keratinous fibres, it is highly desirable to reduce, slow down or indeed even eliminate the penetration of an active agent of the formulation into the substrate, skin or keratinous fibres to which the cosmetic and/or pharmaceutical formulation is applied, either for reasons of safety or for reasons of effectiveness.
Thus, for reasons of effectiveness, it may be important to reduce the penetration of dyes or of sunscreens into the keratinous fibres and/or the skin.
In the case of sunscreens, the protective effect of which on the skin decreases according to their penetration into the skin, it is desirable to slow down, indeed optionally even eliminate, their penetration into the skin in order to increase the effectiveness thereof.
It would thus be desirable to have available an agent which, used with a base cosmetic and/or pharmaceutical composition comprising at least one cosmetically and/or therapeutically active agent, reduces, indeed even eliminates, the penetration into the skin and/or the keratinous fibres of the cosmetically and/or therapeutically active agent.
The above aim is achieved according to the invention by the joint use, with a base cosmetic and/or pharmaceutical composition comprising at least one cosmetically and/or pharmaceutically active agent, of an effective amount of a dispersion of vesicles in a medium, the vesicles comprising at least one ceramide of formula (I): 
in which R1 is chosen from saturated and unsaturated, linear and branched C1-C32, preferably C9-C25, alkyl groups optionally substituted by at least one hydroxyl group, wherein the at least one hydroxyl group is optionally esterified by a group chosen from C1-C35, preferably C8-C28, acyl groups, and R2 is chosen from saturated and unsaturated, linear and branched C1-C50, preferably C6-C35, alkyl groups optionally substituted by at least one hydroxyl group, and wherein the at least one hydroxyl group is optionally esterified by a group chosen from C1-C30, preferably C6-C24, acyl groups.
The medium in which the vesicles are dispersed is essentially an aqueous medium. This means that the medium is sufficiently aqueous so that the vesicles can be dispersed therein.
A subject-matter of the invention is therefore a process for limiting, indeed even eliminating, the penetration into the skin and/or the keratinous fibres of at least one cosmetically and/or pharmaceutically active agent present in a base cosmetic and/or dermal pharmaceutical composition, characterized in that it consists in using, jointly with the base composition, an effective amount of the dispersion of vesicles defined above.
The term xe2x80x9cjoint use of the base composition and of the dispersion of vesiclesxe2x80x9d is understood to mean either the addition of the effective amount of the dispersion of vesicles directly to the base composition before use, such as by application in the form of a film on the skin and/or the keratinous fibres, or the successive application to the skin and/or to the keratinous fibres, in the form of films, of an effective amount of the dispersion of vesicles, followed by the base composition.
The term xe2x80x9ceffective amount of the dispersion of vesiclesxe2x80x9d is understood to mean an amount of the dispersion sufficient to produce a significant effect in limiting the penetration, in particular the rate of penetration, of the active agent or agents of the base composition.
Another subject-matter of the present invention is a cosmetic or pharmaceutical composition which includes at least one cosmetically or pharmaceutically active agent, characterized in that it additionally comprises a dispersion of vesicles as defined above in an amount which is effective in limiting the penetration of the active agent or agents into the skin and/or the keratinous fibres.
The at least one ceramide of the formula (I) is chosen from known compounds. These ceramides and their processes of preparation are disclosed, inter alia, in European Patents EP-500,437, EP-647,617 and EP-790,053, the disclosures of which are specifically incorporated by reference herein.
The dispersion of vesicles can also comprise a mixture of ceramides of formula (I) and/or a stereoisomeric mixture of ceramides of formula (I).
Mention may be made, among the preferred ceramides of formula (I), of
2-(oleoylamino)octadecane-1,3-diol, 2-(lineoylamino)octadecane-1,3-diol,
2-[(2xe2x80x2-hydroxyhexadecanoyl)amino]octadecane-1,3-diol,
2-[(2xe2x80x2-hydroxydecosanoyl)amino]octadecane-1,3-diol,
2-[(D,L-mandeloyl)amino]octadecane-1,3-diol and oleyl chloride.
The particularly preferred ceramide is
2-[(2xe2x80x2-hydroxyhexadecanoyl)amino]octadecane-1,3-diol.
The dispersion of vesicles can comprise at least one second lipids other than the at least one ceramide of formula (I).
The at least one second lipid used in combination with the at least one ceramide of formula (I) in the dispersion of vesicles can be any lipid, other than the at least one ceramide of formula (I) of the dispersion, which makes possible the formation of vesicles and which does not harm the property of limiting penetration of the cosmetically and/or pharmaceutically active agent or agents of the dispersion.
A representative at least one second lipid capable of being used in combination with the at least one ceramide of formula (I), is chosen from alcohols and diols with a chain comprising 8-32 carbon atoms, preferably 12-30 carbon atoms, steroids, such as cholesterol, phospholipids, cholesteryl sulphate and phosphate, amines with a chain comprising 8-32 carbon atoms, preferably 12-30 carbon atoms, and their quaternary ammonium derivatives, dihydroxyalkylamines, polyoxyethylenated amines with a chain comprising 8-32 carbon atoms, preferably 12-30 carbon atoms, esters of aminoalcohols with a chain comprising 8-32 carbon atoms, preferably 12-30 carbon atoms, their salts and quaternary ammonium derivatives, phosphoric esters of alcohols with a chain comprising 8-32 carbon atoms, preferably 12-30 carbon atoms, such as dicetyl hydrogen phosphate and its sodium salt, alkyl sulphates, such as sodium cetyl sulphate, acids with a chain comprising 8-32 carbon atoms, preferably 12-30 carbon atoms, in the form of salts, and lipids of the type of those disclosed in Patents FR-2,315,991, 1,477,048 and 2,091,516 or in International Patent Application WO 93/01571, the disclosures of all of which are specifically incorporated by reference herein.
The term xe2x80x9clipidxe2x80x9d is understood to mean any compound having a chain chosen from saturated and unsaturated, linear and branched, lipophilic chains comprising in particular 8 to 32 carbon atoms, preferably 12 to 30 carbon atoms, for example, oleyl, lanolyl, tetradecyl, hexadecyl, isostearyl, lauryl and alkylphenyl chains. Generally, but not necessarily, these lipids furthermore comprise a hydrophilic chain, which can be an ionic or nonionic group. Mention may be made, as nonionic groups, of groups derived from polyethylene glycol. Use may also be made, as second lipids, of polyglycerol ethers, such as those disclosed in Patents FR-1,477,048, 2,091,516, 2,465,780 and 2,482,128, the disclosures of all of which are specifically incorporated by reference herein.
Use may be made, as ionic groups, of groups chosen from amphoteric, anionic and cationic groups.
The at least one second lipid which can be used in the dispersion of vesicles are representatively chosen from glycolipids, such as lactosylceramide, galactocerebroside, gangliosides and trihexosylceramide, and phospholipids, such as phosphatidylglycerol, phosphatidylinositol, phosphatidylcholine and sphingomyelin.
The at least one second lipid according to the invention can also be representatively chosen from cholesteryl salts, such as cholesteryl sulphates.
The cholesteryl sulphates can be representatively chosen from alkaline sulphates, such as sodium sulphate.
The ratio by weight of the at leasyt one ceramide of formula (I) to the possible at least one second lipid in the dispersion of vesicles generally varies from 80/20 to 20/80, such as from 70/30 to 30/70.
The total concentration of at least one ceramide of formula (I) and the at least one second lipid in the dispersion of vesicles generally varies from 0.05 to 15%, such as from 0.5 to 7.5%, with respect to the total weight of the dispersion.
The dispersion of vesicles can also comprise conventional adjuvants, such as other lipids which are different from the at least one ceramide of formula (I) and the at least one second lipid, emulsifiers, thickeners and solvents.
Representative adjuvants which can be present in the dispersion of vesicles can be chosen from fatty substances, such as mineral, animal and vegetable oils and waxes, fatty acids, fatty acid esters, such as triglycerides of fatty acids having from 6 to 18 carbon atoms and fatty alcohols; emulsifiers, such as oxyethylenated fatty alcohols and polyglycerol alkyl ethers; and solvents, such as lower monoalcohols or polyalcohols comprising 1 to 6 carbon atoms or water.
Specific mono- and polyalcohols are chosen from ethanol, isopropanol, propylene glycol, glycerol and sorbitol.
Representative fatty substances include mineral oils, such as liquid petrolatum; animal oils, such as whale, seal, menhaden, halibut liver, cod, tuna, tortoise, ox hoof, horse hoof, sheep hoof, mink, otter and marmot oils and the like; and vegetable oils, such as almond, wheat germ, olive, maize germ, jojoba, sesame, sunflower, palm, walnut, karite, shorea, macadamia and blackcurrant seed oils and the like.
Representative fatty acid esters can be chosen from esters of saturated and unsaturated C12 to C22 acids and of lower alcohols, such as isopropanol and glycerol, of saturated and unsaturated, linear and branched, C8 to C22 fatty alcohols and of C10-C22 1,2-alkanediols.
Representative fatty substances can be chosen from petrolatum, paraffin, lanolin, hydrogenated lanolin, tallow, acetylated lanolin and silicone oils.
Representative waxes can be chosen from Sipol wax, lanolin wax, beeswax, candelilla wax, microcrystalline wax, carnauba wax, spermaceti, cocoa butter, karite butter, silicone waxes, hydrogenated oils which are solid at 25xc2x0 C., sucroglycerides, Ca, Mg and Al oleates, myristates, linoleates and stearates.
Representative fatty alcohols can be chosen from lauryl, cetyl, myristyl, stearyl, palmityl and oleyl alcohols and Guerbet alcohols, such as 2-octyldodecanol, 2-decyltetradecanol and 2-hexyldecanol.
Representative emulsifying agents can be chosen from polyoxyethylenated fatty alcohols, such as lauryl, cetyl, stearyl and oleyl alcohols comprising from 2 to 20 mol of ethylene oxide and from polyglycerol alkyl ethers, such as C12-C18 alcohols comprising from 2 to 10 mol of glycerol.
It can also be useful to use thickeners, such as cellulose derivatives, polyacrylic acid derivatives, guar gum, locust bean gum or xanthan gum.
The concentration of these adjuvants in the vesicular dispersion generally varies from 0.1 to 20% with respect to the total weight of the dispersion.
The continuous phase of the vesicular dispersion can be representatively chosen from aqueous/alcoholic solutions, water and saline aqueous solutions.
The vesicles generally have a diameter which varies from 0.05 to 5 mm.
The cosmetic and/or pharmaceutical compositions of the process of the invention are all conventional cosmetic and/or pharmaceutical compositions incorporating at least one cosmetically and/or pharmaceutically active agent.
The term xe2x80x9ccosmetically and/or pharmaceutically active agentxe2x80x9d(or xe2x80x9cactive agentxe2x80x9d) is understood to mean any compound or mixture of compounds having a cosmetic and/or pharmaceutical activity.
Representative active agents can be chosen from moisturizing agents, humectants, such as glycerol, sorbitol, pentaerythritol and pyrrolidonecarboxylic acid and its salts; artificial tanning agents, such as dihydroxyacetone, erythrulose, glyceraldehyde and xcex3-dialdehydes for example tartaric aldehyde; water-soluble and liposoluble colorants; water-soluble and liposoluble sunscreens; UV stabilizers; antiperspirants; deodorants; astringents; freshening products; tonics; cicatrizing agents; keratolytic agents; depilatory agents; fragrances and scented waters; plant tissue extracts, such as polysaccharides; antidandruff agents; antiseborrhoeic agents; oxidizing agents, such as bleaching agents, for example aqueous hydrogen peroxide solution; reducing agents, such as thioglycolic acid and its salts; vitamins, such as vitamins E, F or A and their esters; hormones, enzymes, such as superoxide dismutase; antifungals; anti-inflammatories, such as hydrocortisone; antibiotics; bactericides; cytotoxic and antitumour agents; substances intended to improve the condition of dry or senile skin; tocopherols; retinoic acid; antioxidants; essential fatty acids; glycyrrhetinic acid and carotenoids.
The cosmetic and/or dermatological compositions targeted by the present invention can, of course, comprise at least one additional, sunscreen chosen from hydrophilic and lipophilic sunscreens which are active in the UVA and/or UVB regions (absorbers). These additional screening agents can be chosen in particular from cinnamic derivatives, salicylic derivatives, benzylidenecamphor derivatives, benzotriazole derivatives, benzimidazole derivatives, triazine derivatives, benzylmalonic derivatives, b,b-diphenylacrylate derivatives, p-aminobenzoic acid derivatives, and the screening polymers and silicones disclosed in Application WO/93 04665, the disclosure of which is specifically incorporated by reference. Other examples of organic screening agents are given in Patent Application EP-A-0,487,404, the disclosure of which is specifically incorporated by reference.
The preferred active agents are colorants and sunscreens.
The proportion of active agent in the base composition depends on the nature of the active agent and on the desired activity. In general, the at least one active agent represents from 0.05 to 25%, such as 0.5 to 15%, by weight of the base composition.
The base composition can comprise other conventional adjuvants in the conventional proportions. In particular, it can comprise lipids, in particular lipids other than the at least one ceramide of formula (I) described in connection with the vesicular dispersion.
In particular, the base composition can comprise a liquid phase dispersed in an aqueous phase, the constituent(s) of which can be chosen from the group formed by oils, such as esters of fatty acids and of polyols and esters of fatty acids and of branched alcohols of formula R3xe2x80x94COOxe2x80x94R4, in which formula R3 is chosen from residues of higher C7-C19 fatty acids and R4 is chosen from branched C3-C20 hydrocarbonaceous chains; hydrocarbons, such as hexadecane or liquid paraffin; perhydrosqualene; halogenated hydrocarbons, such as perfluorodecahydronaphthalene; perfluorotributylamine; polysiloxanes; esters of organic acids; ethers and polyethers.
This liquid phase can include at least one liposoluble active agent, such as liposoluble sunscreens, tocopherols, vitamins E and F, vitamin A and its esters, retinoic acid, antioxidants, essential fatty acids, glycyrrhetinic acid, keratolytic agents and carotenoids.
The active agents can be dissolved or in the form of a dispersion in the cosmetically and/or pharmaceutically acceptable medium of the base composition. In particular, the active agents can be in the form of a dispersion of vesicles in the medium of the base composition. In the case of water-soluble active agents, they can be present in an aqueous phase encapsulated in vesicles composed of one or more lipids. In the case of liposoluble active agents, they are then found incorporated in the lipid layers of the vesicles.
As indicated above, in the process of the invention, the dispersion of vesicles can be incorporated in the base composition. The incorporation of the dispersion of vesicles can take place either by preparing the dispersion of vesicles and the base composition separately and by combining them in an appropriate fashion or by forming the dispersion of vesicles directly in the base composition during the preparation of the base composition (in situ formation).
In the case of the introduction of a preprepared dispersion of vesicles into a base composition, the amount of dispersion introduced is such that the concentration of the at least one ceramide of formula (I) and of the at least one second lipid in the final composition varies from 0.05 to 15% by weight, such as from 0.5 to 7.5% by weight.
Likewise, when the dispersion of vesicles is formed in situ in the base composition, the total amount of the at least one ceramide of formula (I) and of the at least one second lipid which is introduced is such that the concentration of the at least one ceramide of formula (I) and of the at least one second lipid represents from 0.05 to 15%, such as from 0.5 to 7.5%, by weight of the final composition. In all cases, the ratio by weight of the at least one ceramide of formula (I) to the at least one second lipid varies from 80/20 to 20/80, such as 70/30 to 30/70, in the final compositions.
In the case of the formation of the dispersion of vesicles in situ, during the formulation of the base composition, the at least one active agent can be incorporated in the vesicles of the dispersion of vesicles either in the form of an aqueous solution encapsulated in the lipid phase of the vesicles or in the lipid phase of the vesicles, if the active agent is liposoluble.
The joint use of the dispersion of vesicles and of the base composition can take place by applying first of all the dispersion of vesicles to the skin and/or the keratinous fibres, in order to form a film, and by then applying the base composition comprising the at least one active agent to the film formed.
In this form of use, the dispersion of vesicles and the base composition can be provided in the form of a kit, that is to say be packaged in separate containers present in the same packaging.
The vesicles can be obtained in particular according to the process disclosed in French Patent 2,315,991 of L""Orxc3xa9al, S. A., the disclosure of which is incorporated by reference, according to which a dispersion of vesicles, composed of organized molecular layers including an aqueous phase to be encapsulated, is prepared by bringing into contact, on the one hand, at least one lipid compound, in particular of formula (I), in combination with at least one other lipid, as defined above and, on the other hand, the aqueous phase to be encapsulated in the vesicles, by stirring in order to ensure mixing and to obtain a lamellar phase, by subsequently adding a dispersion liquid in an amount greater than the amount of lamellar phase obtained, and by vigourously shaking for a period of time ranging from 15 minutes to 3 hours approximately.
The ratio by weight of the aqueous dispersion phase which is added to the lamellar phase, which is dispersed, can be from 2:1 to 100:1; the dispersion phase and the aqueous phase to be encapsulated can be isoosmotic.
Stirring can be carried out by means of a shaker. The process can, for example, be carried out at a temperature from 30xc2x0 to 120xc2x0 C.
The dispersion can subsequently be treated by ultrasound and/or be homogenized by a conventional mechanical means.
Another preparation process can comprise using the process known as the REV (reverse-phase evaporation vesicle) process described in Proc. Natl. Acad. Sci. USA., Vol. 75, No. 9, pages 4194-4198 (1978), by Szoka and Papahadjopoulos, the disclosure of which is incorporated by reference.
The process of the invention can be applied in the field of caring for the skin and/or the keratinous fibres, such as the hair, and in the make-up field. In particular, it can advantageously be applied in the field of protecting against sunlight, where, by slowing down penetration of the sunscreen into the skin, it prolongs the protective activity of the screening agent, and in the field of colouring the hair, where it restricts the penetration of colorants into the skin and/or the scalp.
In the following examples, which illustrate the present invention, all percentages and parts are expressed by weight, unless otherwise indicated.